text: The ProTide pro-drugs are useful for delivering phosphonate containing drugs to cell types with high expression of CTSA and CES1, such as immune cells. Tenofovir alafenamide is a successful example of this iteration. ProTides are also useful for nucleoside analogues that do not get phosphorylated efficiently by endogenous nucleoside kinases. For the nucleoside GS-334750, the parent of sofosbuvir, phosphorylation by nucleoside kinases is effectively nilled, and the only way to deliver active nucleotide is through ProTide. A major limitation of ProTides is that they require an expression of esterases like CTSA and CES1, which is very high in some cell types like hepatocytes and plays to an advantage for the treatment of Hepatitis C of Sofosbuvir.
  Extensive studies followed on these promising d4T derivatives and the ProTide technology was successfully applied to a wide range of nucleoside analogues. In particular, the ProTide approach has been used on several clinically evaluated anti-HCV nucleoside analogues, including the 2013 FDA approved compound sofosbuvir, and the 2016 FDA approved compound, Tenofovir alafenamide. Remdesivir, the only anti-viral FDA-approved to treat COVID-19 also uses the ProTide prodrug technology (self-immolation is the key principle of ProTide nucleotide prodrugs). Because GS-441524 nucleoside can be phosphorylated and activated, some researchers have argued that the Protide application is an unnecessary complication in Remdesivir's design and that the parent nucleoside would be a cheaper and more effective COVID-19 drug.
  ProTides have been tested to deliver key phosphorylated metabolites in inborn errors of metabolism, such as phosphopantothenate for PANK2 deficiency, however these were a clinical failure.